Rapamycin (molecular formula: C51H79NO13, molecular weight: 914.2), also known as sirolimus, is a macrolide lactone-based compound. It has an immunosuppressive activity and so has been commercialized as a transplant rejection inhibitor (Rapamune) for organ transplant patients. As well as for inhibiting the organ transplant rejection, rapamycin can be used for treating pulmonary inflammation, systemic lupus erythematosis, immunoinflammatory skin disorders including psoriasis, immunoinflammatory bowel disorders, ocular inflammation, restenosis, rheumatoid arthritis, etc.
Recently, it has been reported that in addition to the function of the immunosuppressive agent, rapamycin has the function of an anticancer agent which acts as an inhibitor of mammalian target of rapamycin (mTOR) to induce apoptosis and destroy cancer cells thereby. However, since rapamycin has a very low solubility in water (1 to 2 μg/ml), it shows a very low absorption rate upon oral administration and has a great variance in bioavailability between individuals.
Rapamune tablet has been introduced as a formulation containing rapamycin. This tablet comprises excipients including sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, povidone, poloxamer 188, glyceryl monooleate, etc. In addition, Rapamune oral solution comprises Phosal 50 PG (phosphatidyl choline, propylene glycol, mono-glyceride, di-glyceride, ethanol, soy bean fatty acid, ascorbyl palmitate) and polysorbate 80, with 1.5 to 2.5% of ethanol content.
When Rapamune oral solution is orally administered to human patients, the absolute bioavailability is about 14%. When Rapamune tablet is orally administered, the absolute bioavailability is relatively higher by about 25% as compared with the oral administration Rapamune oral solution. However, both formulations show low absolute bioavailability below 20% and this is due to the low solubility of rapamycin in water.
Therefore, various attempts have been made to formulate rapamycin using various solubilization techniques. U.S. Pat. No. 5,559,121 discloses a capsule formulation composition containing a solution of rapamycin wherein rapamycin is dissolved in a mixed solution comprising polysorbate 80 surfactant, N,N-dimethylacetamide, and either lecithin or phospholipid. U.S. Pat. No. 5,616,588 discloses an injectable aqueous solution of rapamycin wherein rapamycin is dissolved in an aqueous solution of propylene glycol at a concentration of 0.1 to 4 mg/ml, without containing non-ionic surfactant. However, the known injectable aqueous solutions of rapamycin have a poor stability as an aqueous solution and thus should be administered within a short period of time. No injectable formulations are commercially available at present.
Korean Patent No. 0160957 discloses a composition for inhibiting organ or tissue transplant rejection, which comprises rapamycin in an effective amount for inhibiting mammalian organ or tissue transplant rejection. However, in this patent, rapamycin is used together with oils such as olive oil, alcohols, propylene glycols, and polyethylene glycols and surfactants such as Cremophor EL and polysorbate 80.
As a technique for solubilizing poorly soluble drugs, U.S. Pat. Nos. 6,322,805 and 6,616,941 disclose a polymeric micelle using an amphiphilic block copolymer in which a hydrophilic polyethylene glycol (A) block and a hydrophobic polylactide (B) block are combined in the form of an A-B type diblock. However, no specific examples to solubilize rapamycin with said polymeric micelle have been provided therein.